The purpose of this STTR Phase 1 application is to obtain proof-of-concept evidence that supports the indication of lobeline for the treatment of adult Attention Deficit Hyperactivity Disorder (ADHD). Research on the neurobiology of ADHD implicates abnormalities in brain dopamine (DA) and norepinephrine (NE) and possibly in nicotinic receptors. Currently available stimulant medications reverse the core behavioral symptoms and neurocognitive deficits that characterize ADHD, but are not without limitations or risks. Lobeline is a nonstimulant alkaloid shown in preclinical studies to alter DA and NE neurotransmission by interacting with the vesicular monoamine transporter (VMAT2) and acts as a nicotinic receptor antagonist. Lobeline inhibits hyperactivity induced by nicotine and amphetamine. Preclinical studies demonstrate that lobeline decreases the reinforcing effects of methamphetamine, suggesting that it will not increase the use of drugs of abuse. Furthermore, lobeline has been found to be safe in clinical trials. In the proposed initial proof- of-concept, human laboratory study, the physiological and behavioral effects of a range of doses of lobeline will be assessed in adults with ADHD. Particular emphasis will be made to task measures of attention, impulsivity and working memory. In addition, subjective effects related to abuse liability and drug tolerability will be assessed. We hypothesize that lobeline will decrease inattention and impulsivity and enhance working memory in adults with ADHD. We expect lobeline to be well tolerated and not to engender changes in self- report measures associated with abuse liability. Methylphenidate will be evaluated as a positive control to provide confirmation that the measures of inattention, impulsivity and working memory are sensitive to therapeutic drug effects. Results from the proposed study will provide proof-of-concept that lobeline has potential as an efficacious non-stimulant medication for ADHD. If improvements on outcome measures of attention and memory are obtained with lobeline, we will advance to a human clinical trial to demonstrate the efficacy of lobeline in an ADHD population. This project supports the development of a safe and effective non-stimulant medication for the treatment of adult Attention Deficit Hyperactivity Disorder. The study will evaluate the ability of lobeline to improve the hallmark symptoms of ADHD, including inattention, impulsivity and memory problems. Also, lobeline will be assessed for side-effects and abuse liability. Information obtained from the proposed study will inform subsequent clinical trials aimed at determining if lobeline is a useful and efficacious treatment for adult ADHD. [unreadable] [unreadable] [unreadable]